FDA Advisors Tilt Toward New Lung Ca Drug

One member calls it a necessary 'baby step' forward in NSCLC care.

SILVER SPRING, Md. -- Most members of an FDA's advisory committee meeting Thursday favored approval for necitumumab, a monoclonal antibody that targets epidermal growth factor receptors (EGFR) in non-small cell lung cancer patients on Thursday, though not without dissent.

While the committee did not tally an official vote, the majority said that recent trial data demonstrated a positive benefit-risk profile for the agent; but a few members weighed the drug's known and unknown risks more heavily against the relatively modest survival improvement.

The FDA's Oncologic Drugs Advisory Committee met to discuss the application submitted for necitumumab for use in conjunction with gemcitabine and cisplatin. The agent is intended "for the first line treatment of patients with locally advance or metastatic squamous non-small cell lung cancer (NSCLC)," noted the FDA's technical staff in briefing documents released earlier this week.

She added, "When I am talking to patients who are going on trials, they all want a magic bullet or a home run, but frankly we tend to build in small baby steps and move forward that way, and this would have to be considered one of those [times]."

In Lilly's presentation, the company's representatives repeatedly said there have not been any significant advances in treatment for squamous NCLC for the last 2 decades -- although the FDA did approve nivolumab (Opdivo) for squamous NSCLC in March.

Some panel members disagreed with Armstrong's overall assessment. Antonio "Tito" Fojo, MD, PhD, of the National Cancer Institute in Bethesda, Md., said, "At the end of the day this trial doesn't provide me the comfort of saying that the risk-benefit is a favorable one."

Fojo said he would need "better data and additional data" before recommending the FDA move forward with the drug.

At the 2014 meeting of the American Society of Clinical Oncology (ASCO), the SQUIRE trial of necitumumab taken with conventional chemotherapy demonstrated a statistically significant 6-week improvement in overall survival (OS) among patients whose squamous NSCLC was previously untreated versus those given chemotherapy alone. Overall survival rates were a median of 11.5 months for necitumumab subjects versus 9.9 months in the control group. The ASCO's criteria for clinically-meaningful difference is 2.5 to 3 months for patients with squamous cell carcinoma, despite a statistically significant 16% increase in survival, the agent failed to meet this threshold.

The INSPIRE trial, a similarly designed open-label randomized study, did not result in any improvements in overall survival and was terminated early following the recommendation of an independent governing board, due to a safety signal around thromboembolic events.

In addition, patients given necitumumab in the trials showed a higher risk of serious skin reactions, hypomagnesemia, and thromboembolic events, as well as a slightly increased risk of sudden death (2.2% vs. 0.5% in SQUIRE and 3.6% vs. 1.6% in INSPIRE), according to briefing documents. While the cause of death was unclear, an imbalance in electrolyte associated with necitumumab and platinum therapy, along with comorbid illness, may have been a driving factor, noted FDA staff.

The most common embolic events were pulmonary emboli, deep vein thrombosis, myocardial infarction, and cerebrovascular accidents.

Panel member Bruce Roth, MD, a professor of medicine at the Washington University School of Medicine said he didn't want to base his support for a drug's benefit on interventions that may or may not happen down the road. "I could certainly hypothesize for every [venous thromboembolism] that we successfully prophylax with anticoagulation we have another bleeding death." Roth said he didn't want the panel to try to make itself feel good about potential risks by naming solutions, "when we may not even be addressing the right issues, much less ... successfully treating the ones that we've identified."

Hossein Borghaei, DO, head of thoracic oncology at the Fox Chase Cancer Center at Temple Health in Philadelphia, and not a member of the committee, told MedPage Today in an email, "I think that from a risk-benefit standpoint the addition of this drug to standard chemotherapy increases potential toxicities such as thromboembolic events for a slight improvement in overall survival. As a practicing thoracic medical oncologist I don't think I will be using this drug, if approved, in the treatment of my patients with squamous cell carcinoma of the lung."

Lilly proposed a management plan for the drug that included monitoring for electrolyte imbalances before each infusion and labeling that would suggest physicians "carefully consider use of necitumumab in patients with a history of coronary artery disease or arrhythmias." It also proposed education and awareness programs to provide risk information to patients and providers and a possible safety study of thromboembolic events.

The FDA is not required to follow the recommendations of advisory committees but it often does.

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